Methods for activating PPAR gamma-type receptors

ABSTRACT

Novel biaromatic compounds having the following structural formula (I): 
     
       
         
         
             
             
         
       
     
     are formulated into pharmaceutical compositions suited for administration in human or veterinary medicine, in particular in dermatology as well as in the fields of cardiovascular diseases, immune diseases and/or diseases related to the metabolism of lipids, or, alternatively, into cosmetic compositions.

CROSS-REFERENCE TO EARLIER APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.11/592,276 filed Nov. 3, 2006, which is a continuation of PCT/EP2005/005797 filed Apr. 29, 2005 and designating the United States,published in the English language as WO 2005/108352 A1 on Nov. 17, 2005,which claims the benefit of U.S. Provisional Application No. 60/574,217,filed May 26, 2004 and also claims priority of FR04/04913, filed May 6,2004 in France, each hereby expressly incorporated by reference and eachassigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to a novel class of biaromatic compoundswhich are activators of receptors of “Peroxisome Proliferator-ActivatedReceptor” type of subtype γ (PPARγ). This invention also relates totheir process of preparation and to their formulation intopharmaceutical compositions suited for human or veterinary medicine, oralternatively for cosmetic compositions.

2. Description of Background and/or Related and/or Prior Art

The activity of receptors of PPAR type has been the subject of manystudies. Mention may be made, by way of indication, of the publicationentitled “Differential Expression of Peroxisome Proliferator-ActivatedReceptor Subtypes During the Differentiation of Human Keratinocytes”,Michel Rivier et al., J. Invest. Dermatol., 1998, 111, 1116-1121, inwhich a large number of bibliographic references relating to receptorsof PPAR type are listed. Mention may also be made, by way of indication,of the report entitled “The PPARs: From Orphan Receptors to DrugDiscovery”, Timothy M. Willson et al., J. Med. Chem., 2000, 43, 527-550.

PPAR receptors activate transcription by binding to elements of DNAsequences, known as peroxisome proliferator response elements (PPRE), inthe form of a heterodimer with retinoid X receptors (known as RXRs).

Three subtypes of human PPARs have been identified and described: PPARα,PPARγ and PPARδ (or NUC1).

PPARα is mainly expressed in the liver, while PPARδ is ubiquitous.

PPARγ is the most widely studied of the three subtypes. All prior artreferences suggest a critical role for PPARγ in the regulation of thedifferentiation of adipocytes, where it is greatly expressed. It alsoplays a key role in systemic lipid homeostasis.

Furthermore, the assignee hereof has already disclosed, in FR 98/02894,the use of PPARγ-activating compounds in the preparation of apharmaceutical composition, the composition being intended for thetreatment of skin disorders related to an anomaly in the differentiationof the epidermal cells.

The assignee hereof has also disclosed a class of biaromatic compoundswhich are activators of PPARγ receptors in FR-2,812,876.

SUMMARY OF THE INVENTION

A novel class of PPARγ-activating compounds has now been developedexhibiting biological activities which are significantly improved withrespect to those of the compounds known to the prior art and inparticular with respect to those described in FR-2,812,876.

According to the present invention, a restricted group of compounds hasnow been developed, corresponding to the formula (I) below, whichexhibit a surprising biological activity, in particular a bindingaffinity for PPARγ receptors which is significantly increased withrespect to that of the compounds of FR-2,812,876. This increased bindingaffinity emerges in particular from apparent dissociation constant(KdApp) values which are surprisingly lowered, as more fully explainedbelow.

Thus, the present invention features novel compounds corresponding tothe following general formula (I):

in which:

R1 is an alkyl radical having 1 to 6 carbon atoms, an acetyl group, amethylcyclopropane group, an aralkyl radical or an aryl radical;

R2 is an alkyl radical having 3 to 8 carbon atoms;

R3 is a hydrogen atom or an alkyl radical having 1 to 6 carbon atoms;

R4 and R5, which may be identical or different, are each a hydrogenatom, a halogen atom, a hydroxyl radical, an alkyl radical having from 1to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or atrifluoromethyl radical;

and the isomers, optical and/or geometrical, pure or as a mixture, inall proportions, of the said compounds of formula (I) and the tautomericforms, and also the salts of the said compounds of formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1 and 2 illustrate a variety of reaction schemes for thepreparation of the compounds according to the present invention.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OFTHE INVENTION

For the compounds of formula (I) which is presented above, the term“geometrical isomer” means cis/trans or E/Z isomerism. Moreparticularly, the possible double bond or bonds present in the varioussubstituents of the compounds of general formula (I) can be of E or Zconfiguration. These geometrical isomers, pure or impure, alone or as amixture, are an integral part of the compounds of formula (I).

The term “optical isomer” embraces all the forms of isomers, alone or asa mixture, the presence of which results from one or more axes and/orcentres of symmetry in the molecule which results in the rotation of abeam of polarized light. The term “optical isomer” comprises moreparticularly the enantiomers and the diastereoisomers, in the pure formor as a mixture.

When the compounds according to the invention are provided in the formof a salt, they are preferably an alkali metal salt, in particular thesodium salt, or an alkaline earth metal salt or an organic amine salt,more particularly of amino acids, such as arginine or lysine.

According to the present invention, the term “alkyl radical having from1 to 6 carbon atoms” means, preferably, an optionally branched,saturated or unsaturated, linear or cyclic alkyl radical selected fromthe methyl, ethyl, n-propyl, isopropyl, cyclopropyl, n-butyl, isobutyl,tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclohexyl,ethylenyl, allyl, propenyl, butenyl, pentenyl or hexenyl radicals.

According to the present invention, the term “alkyl radical having from3 to 8 carbon atoms” means, preferably, an optionally branched,saturated or unsaturated, linear or cyclic alkyl radical comprising 3 to8 carbon atoms and preferably the n-propyl, isopropyl, cyclopropyl,n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, cyclopentyl,n-hexyl, isohexyl, cyclohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl,allyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl or octenylradicals.

The term “halogen atom” means, preferably, a fluorine, chlorine orbromine atom.

The term “aralkyl radical” means, preferably, a benzyl, phenethyl ornaphth-2-ylmethyl radical which is unsubstituted or substituted by oneor more radicals selected from among a halogen atom, a CF₃ radical, analkyl radical having from 1 to 6 carbon atoms, an alkoxy radical havingfrom 1 to 6 carbon atoms, a hydroxyl radical or an amino functionalgroup which is unprotected or unsubstituted or optionally substituted byat least one alkyl radical having from 1 to 6 carbon atoms, or acarboxyl functional group.

The term “aryl radical” means, preferably, a phenyl, biphenyl, cinnamylor naphthyl radical which can be mono- or disubstituted by a halogenatom, a CF₃ radical, an alkyl radical having from 1 to 6 carbon atoms,an alkoxy radical having from 1 to 6 carbon atoms, a nitro functionalgroup, a polyether radical, an aryl radical, a benzoyl radical, an alkylester group, a carboxylic acid, a hydroxyl radical optionally protectedby an acetyl or benzoyl group, or an amino functional group optionallyprotected by an acetyl or benzoyl group or optionally substituted by atleast one alkyl having from 1 to 6 carbon atoms.

The term “alkoxy radical” means, preferably, a methoxy, ethoxy,isopropyloxy, tert-butoxy, hexyloxy, benzyloxy or phenoxy radical whichcan optionally be substituted by an alkyl radical having from 1 to 6carbon atoms.

The term “polyether radical” means, preferably, a radical having from 1to 6 carbon atoms which is interrupted by at least one oxygen atom, suchas the methoxymethoxy, methoxymethylene, ethoxymethoxy, ethoxymethyleneor methoxyethoxymethoxy radicals.

The term “alkyl ester radical” means a carboxylate functional groupsubstituted by an alkyl radical having from 1 to 6 carbon atoms.

Among the compounds of formula (I) above within the scope of the presentinvention, the following compounds (alone or as a mixture) areparticularly exemplary:

-   1.    2(S)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   2.    2(S)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   3.    2(S)-Cyclopropylmethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   4.    2(S)-Propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   5.    2(S)-Benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   6.    2(S)-Allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   7.    2(S)-Cyclopropylmethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   8.    3-[3′-(1-Methyl-3-pentylureido)biphenyl-4-yl]-2(S)-propoxypropanoic    acid,-   9.    2(S)-Allyloxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   10.    2(S)-Benzyloxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   11.    2(S)-Methoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   12.    3-[3′-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropanoic    acid,-   13.    2(S)-Ethoxy-3-[3′-(1-methyl-3-propylureido)biphenyl-4-yl]propanoic    acid,-   14.    3-[3′-(3-Cyclopropylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic    acid,-   15.    3-[3′-(3-Cyclopentylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic    acid,-   16.    2(S)-Ethoxy-3-[3-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   17.    2(S)-Ethoxy-3-[4′-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   18.    3-[3,4′-Difluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic    acid,-   19. Methyl    2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate,-   20. Methyl    2(S)-cyclopropylmethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate,-   21.    2(S)-Cyclopropylmethoxy-3-[3′-(3-cyclopropylmethyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   22.    3-{3′-[3-(2-Cyclohexylethyl)-1-methylureido]biphenyl-4-yl}-2(S)-ethoxypropanoic    acid,-   23.    2(R)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic    acid,-   24.    2(R)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   25. 2-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   26.    2(R)-Allyloxy-3[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic    acid,-   27.    3-[3′-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic    acid,-   28. Allyl    3-[3′-(3-allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoate.

According to the present invention, the compounds of formula (I) whichare more particularly preferred are those which exhibit at least one ofthe following characteristics:

R1 is an alkyl radical selected from among the methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl or tert-butyl radicals, amethylcyclopropane group or a benzyl radical,

R2 is an alkyl radical selected from among the n-pentyl, isopentyl,cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptylradicals,

R3 is a hydrogen atom,

R4 and/or R5 are a hydrogen atom or a fluorine atom.

In particular, according to the present invention, preferred are thecompounds of formula (I) exhibiting all of the followingcharacteristics:

R1 is an alkyl radical selected from among the methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, isobutyl or tert-butyl radicals, amethylcyclopropane group or a benzyl radical,

R2 is an alkyl radical selected from among the n-pentyl, isopentyl,cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptylradicals,

R3 is a hydrogen atom,

R4 and/or R5 are a hydrogen atom or a fluorine atom.

More particularly, the present invention features a process for thesynthesis of the compounds corresponding to the general formula (I) orof the possible isomers, optical and/or geometrical, pure or as amixture, in all proportions, of the said compounds of formula (I), ofthe possible tautomeric forms, or of the salts of the said compounds offormula (I), comprising the following stages:

in the stages described below, which relate to FIG. 1, unless otherwiseindicated, the R1, R2, R3, R4 and R5 radicals of the compounds 1 to 20are the same as those defined for the compounds of general formula (I).

a) Preparation of the Compound of Formula 1:

from commercial 3-bromoaniline optionally substituted by an R5 group, byprotecting the amine with di(tert-butyl) dicarbonate and by thencarrying out a methylation, for example with methyl iodide, in thepresence of sodium hydride;

b) Preparation of Compound 2:

by treating compound 1 with an acid, such as, for example,trifluoroacetic acid;

c) Preparation of Compound 3:

by the reaction of compound 2 with pinacolborane in the presence of acatalyst, such as palladium dichloride diphenylphosphinopropaneferrocene;

d) Preparation of Compound 5:

by treating the commercial epoxide 4:

with an aryl cuprate obtained by reaction of an aryl halide, such as,for example, 1,4-dibromobenzene, in the presence of tert-butyllithiumand of copper cyanide;

e) Preparation of Compound 6:

by reacting compound 5 with an alkyl halide, such as ethyl iodide, forexample, in the presence of silver oxide, to prevent any problem ofracemization;

f) Preparation of Compound 7:

by the coupling of compound 6 and compound 3 according to a reaction ofSuzuki type in the presence of tetrakis(triphenylphosphine)palladium;

g) Preparation of Compound 8:

by the reaction from compound 7 and an alkyl isocyanate, such as, forexample, heptyl isocyanate;

h) Preparation of Compound (I):

h1) when R3 is an alkyl radical: by transesterification of compound 8with an alcohol in the presence of an acid, such as sulfuric acid, or

h2) when R3 is a hydrogen atom: by saponification of compound 8 in thepresence of a base, such as, for example, sodium hydroxide.

According to another advantageous process for the synthesis of thecompounds of formula (I), the stages for preparing compound 3 arerepeated as defined in parts a) to c) and the stages for preparingcompound 5 are repeated as defined in part d) and are followed by thestages set out below:

i) Preparation of Compound 10:

by treating compound 5 with a benzyl halide, such as, for example,benzyl bromide, in the presence of silver oxide;

j) Preparation of compound 11:

by coupling compound 10 with compound 3 by a reaction of Suzuki typeusing a palladium catalyst, such as, for example,tetrakis(triphenylphosphine)palladium;

k) Preparation of Compound 12:

by the reaction from compound 11 and an alkyl isocyanate, such as, forexample, heptyl isocyanate;

l) Preparation of the Alcohol 13:

by hydrogenolysis of compound 12 with hydrogen in the presence ofpalladium-on-charcoal;

m) Preparation of Compound 8:

by reacting compound 13 with an alkyl halide, such as allyl bromide, forexample, in the presence of silver oxide;

n) Preparation of Compound (I) from Compound 8 as Defined in Stage h),the Alternatives n1) and n2) being Identical to the Alternatives h1) andh2).

The compounds of formula (I) can also be obtained according to thereaction scheme presented by the synthetic route 2 a of FIG. 2 fromaldehyde derivatives 15 according to a reaction of Horner type with aphosphonate 16 in the presence of a base, such as sodium hydride,butyllithium or potassium tert-butoxide, then hydrogenation in thepresence of palladium-on-charcoal and optionally enzymatic resolution,for example in the presence of the enzyme proteinase 2A, to obtain the(S) enantiomer. According to this method of synthesis, R1, R2, R3, R4and R5 are as defined above.

The compounds of formula (I) can also be obtained according to thereaction scheme presented by the synthetic route 2 b of FIG. 2 by thereaction of 4(S)-benzyloxazolidin-2-one and of a 2-alkoxyacetic acidchloride for the preparation of an Evans derivative, followed by thecondensation of such an Evans derivative, of well-defined chirality,with the aldehyde derivative 15 in the presence of dibutylborontriflate, for example, which results in the derivative 19. Thedeoxygenation of compound 19 by the Barton reaction results in compound20. Compound (I) is obtained from compound 20 by saponification, forexample in the presence of lithium hydroxide, or by transesterification,for example with sodium methoxide in methanol. According to this methodof synthesis, R1, R2, R3, R4 and R5 are as defined above.

According to the present invention, the term “Evans derivative” means,preferably, an oxazolidin-2-one derivative of well-defined chirality,such as a 4(S)-benzyloxazolidin-2-one derivative.

According to the present invention, the term “Barton reaction” means thereaction of phenyl chlorothionoformate with the hydroxyl group ofcompound 19, in the case of the synthetic route 2 b considered in FIG.2, followed by a radical reaction in the presence of tributyltinhydride.

The compounds according to the invention exhibit modulatory propertieswith regard to receptors of PPAR type. This activity on PPARα, δ and γreceptors is measured in a transactivation test and quantified by theapparent dissociation constant (KdApp), as described in Example 7 below.

In a manner not obvious to one skilled in the art in the light of theprior art, the preferred compounds according to the invention exhibit asurprising biological activity, in particular a binding affinity forPPARδ receptors which is significantly increased with respect to that ofthe compounds according to FR-2,812,876. The KdApp values of thecompounds according to the present invention for PPARγ receptors arelisted in Example 7 and are illustrated in Table 1, where they arecompared with those of the compounds of FR-2,812,876: it is apparentthat they are less than 1 nM and advantageously less than 0.1 nM, i.e.,at least 120 times lower and up to several thousand times lower than theKdApp values described for the compounds of FR-2,812,876 (Table 1),reflecting a considerably increased affinity of the compounds accordingto the present invention for PPARγ receptors. In Table 1, the KdAppvalues, with PPARγ receptors, of certain compounds according to theinvention are compared with certain compounds according to the priorart, the compounds exhibiting similar substituents being considered. Inparticular, the R1 radical according to the invention is equivalent tothe R10 radical of the compounds according to FR-2,812,876 and the R2radical according to the invention is equivalent to the R4 radical ofthe compounds according to FR-2,812,876.

In particular, the compounds according to the invention are modulatorsof specific receptors of PPARγ type, that is to say that they exhibit aratio of the KdApp for the PPARα or PPARδ receptors to the KdApp for thePPARγ receptors of greater than or equal to 10. Preferably, thisPPARα/PPARγ or PPARδ/PPARγ ratio is greater than or equal to 50 and moreadvantageously greater than or equal to 100.

The present invention also features the compounds of formula (I) asdescribed above as medicaments.

The compounds according to the invention are particularly well suitedfor the following treatments:

1) of dermatological conditions linked to a disorder of keratinizationinvolving differentiation and proliferation, in particular for treatingacne vulgaris, comedonic or polymorphic acne, acne rosacea, nodulocysticacne, acne conglobata, senile acne and secondary acnes, such as solar,drug or occupational acne,

2) of other types of disorders of keratinization, in particularichthyoses, ichthyosiform conditions, Darrier's disease, palmoplantarkeratoderma, leucoplakia and leucoplakiform conditions or cutaneous ormucosal (oral) lichen,

3) of other dermatological conditions or afflictions having aninflammatory immunoallergic component, with or without cellproliferation disorder, and, in particular, all forms of psoriasis,whether cutaneous, mucosal or ungual, and even psoriatic rheumatism, oralternatively cutaneous atopy, such as eczema, or respiratory atopy oralternatively gingival hypertrophy,

4) of all dermal or epidermal proliferations, whether they are benign ormalignant and whether they are or are not of viral origin, such ascommon warts, flat warts and epidermodysplasia verruciformis, florid ororal papillomatoses, T lymphoma, and the proliferations which can beinduced by ultraviolet radiation, in particular in the case of basalcell and prickle cell epithelioma, and also all precancerous skinlesions, such as keratoacanthomas,

5) of other dermatological disorders, such as immune dermatoses, such aslupus erythematosus, immune bullous diseases and collagen diseases, suchas scleroderma,

6) of dermatological or general conditions or afflictions having animmunological component,

7) of skin disorders due to exposure to UV radiation, and also forrepairing or combating skin aging, whether photoinduced or chronologicor for reducing actinic keratoses and pigmentations or any pathologyassociated with chronologic or actinic aging, such as xerosis,

8) of disorders of the sebaceous function, such as hyperseborrhoea ofacne or simple seborrhoea,

9) or the prevention of disorders of cicatrization or the prevention orthe repair of stretch marks,

10) of disorders of pigmentation, such as hyperpigmentation, melasma,hypopigmentation or vitiligo,

11) of conditions of the metabolism of lipids, such as obesity,hyperlipidaemia or non-insulin-dependent diabetes,

12) of inflammatory conditions, such as arthritis,

13) or the prevention of cancerous or precancerous conditions,

14) or the prevention of alopecia of various origins, in particularalopecia due to chemotherapy or to radiation,

15) of disorders of the immune system, such as asthma, type I diabetesmellitus, multiple sclerosis or other selective dysfunctions of theimmune system,

16) of conditions of the cardiovascular system, such as arteriosclerosisor hypertension.

The present invention also features pharmaceutical or cosmeticcompositions comprising, formulated into a physiologically acceptablemedium, at least one compound of formula (I) as defined above.

This invention also features the use of the compounds of formula (I) inthe manufacture of compositions suited for the treatment of theabovementioned conditions, in particular for regulating and/or restoringthe metabolism of skin lipids.

The compositions according to the invention can be administered orally,parenterally, topically or ocularly. Preferably, the pharmaceuticalcomposition is packaged in a form suitable for topical application.

Orally, the composition, more particularly the pharmaceuticalcomposition, can be provided in the form of tablets, includingsugar-coated tablets, hard gelatin capsules, syrups, suspensions,solutions, powders, granules, emulsions or lipid or polymericmicrospheres or nanospheres or vesicles which make possible controlledrelease. Parenterally, the composition can be provided in the form ofsolutions or suspensions for infusion or for injection.

The compounds according to the invention are generally administered at adaily dose of approximately 0.001 mg/kg to 100 mg/kg of body weight,taken 1 to 3 times.

The compounds are administered systemically at a concentration generallyof from 0.001% to 10% by weight, preferably from 0.01% to 1% by weight,with respect to the weight of the composition.

Topically, the pharmaceutical composition according to the invention ismore particularly suited for the treatment of the skin and mucousmembranes and can be provided in the form of salves, creams, milks,ointments, powders, impregnated pads, solutions, gels, sprays, lotionsor suspensions. It can also be provided in the form of lipid orpolymeric microspheres or nanospheres or vesicles or of polymericpatches and of hydrogels which make possible controlled release. Thistopical composition can be provided in the anhydrous form, in theaqueous form or in the form of an emulsion.

The compounds are administered topically at a concentration generally offrom 0.001% to 10% by weight, preferably from 0.01% to 1% by weight,with respect to the total weight of the composition.

The compounds of formula (I) according to the invention also have anapplication in the cosmetics field, in particular in body and hairhygiene and more particularly for regulating and/or restoring themetabolism of skin lipids. In comparison with the products knownpreviously, these compounds of formula (I) have the advantage ofadditionally exhibiting other advantageous properties, in particularanti-inflammatory or soothing properties, which makes them lessirritating and therefore better tolerated compounds.

The present invention also features the cosmetic use of a compositioncomprising, formulated into a physiologically acceptable vehicle, atleast one of the compounds of formula (I) for body or hair hygiene.

The cosmetic compositions according to the invention, comprising, in acosmetically acceptable vehicle, at least one compound of formula (I) orone of its optical or geometrical isomers or one of its salts, can beprovided in particular in the form of a cream, a milk, a lotion, a gel,lipid or polymeric microspheres or nanospheres or vesicles, a soap or ashampoo.

The concentration of compound of formula (I) in the subject cosmeticcompositions ranges from 0.001% to 3% by weight, with respect to thetotal weight of the composition.

The compositions as described above can, of course, additionallycomprise inert or even pharmacodynamically active additives orcombinations of these additives and in particular: wetting agents;depigmenting agents, such as hydroquinone, azelaic acid, caffeic acid orkojic acid; emollients; moisturizing agents, such as glycerol,polyethylene glycol (PEG) 400, thiamorpholinone and its derivatives, orurea; anti-seborrhoeic or anti-acne agents, such asS-carboxymethylcysteine, S-benzylcysteamine, their salts or theirderivatives, or benzoyl peroxide; anti-fungal agents, such asketoconazole or 4,5-polymethylene-3-isothiazolidones; anti-bacterials;carotenoids and in particular β-carotene; anti-psoriatic agents, such asanthralin and its derivatives; eicosa-5,8,11,14-tetraynoic andeicosa-5,8,11-triynoic acids, their esters and amides; and, finally,retinoids. The compounds of formula (I) can also be combined withvitamins D or their derivatives, with corticosteroids, with agents forcombating free radicals, with α-hydroxy or a-keto acids or theirderivatives, or with ion-channel blockers.

These compositions can also comprise flavor enhancers, preservatives,such as esters of para-hydroxybenzoic acid, stabilizing agents,moisture-regulating agents, pH-regulating agents, agents for modifyingosmotic pressure, emulsifying agents, UV-A and UV-B screening agents, orantioxidants, such as α-tocopherol, butylated hydroxyanisole orbutylated hydroxytoluene.

Of course, one skilled in this art will take care to select the optionalcompound or compounds to be added to these compositions so that theadvantageous properties intrinsically associated with the presentinvention are not, or not substantially, detrimentally affected by theenvisaged addition.

The present invention also features a cosmetic regime or regimen forrendering the skin more attractive, wherein a composition comprising atleast one compound of formula (I) as defined above is topically appliedonto the skin. The regulation and/or the restoration of the metabolismof skin lipids makes it possible to obtain skin with a surfaceappearance which has been rendered more attractive.

In order to further illustrate the present invention and the advantagesthereof, the following specific examples of active compounds are given,as are the results of the biological activities thereof, it beingunderstood that same are intended only as illustrative and in nowiselimitative. In said examples to follow, all parts and percentages aregiven by weight, unless otherwise indicated.

Example 1 Synthesis of2(S)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid

a) Preparation of tert-Butyl (3-bromophenyl)carbamate:

120 g (549 mmol) of di(tert-butyl) dicarbonate are added in smallamounts at ambient temperature to a mixture of 94 g (549 mmol) of3-bromoaniline and 1 l of dichloromethane. After stirring for 18 hours,the reaction mixture is poured into ice-cold water and extracted withdichloromethane. The organic phase is separated by settling, dried overmagnesium sulfate and evaporated. 138 g of tert-butyl(3-bromobenzyl)carbamate are obtained. Yield=98%.

b) Preparation of tert-Butyl (3-bromophenyl)-N-methylcarbamate:

19 g (475 mmol) of sodium hydride (60% in oil) are added in smallamounts to a solution of 114 g (447 mmol) of tert-butyl(3-bromobenzyl)carbamate in 800 ml of dimethylformamide and the reactionmedium is stirred until evolution of gas has ceased. 29.3 ml (470 mmol)of methyl iodide are added dropwise and stirring is maintained for 18hours. The reaction medium is poured into ice-cold water and extractedwith ethyl acetate. The organic phase is separated by settling, driedover magnesium sulfate and evaporated. 115 g of tert-butyl(3-bromobenzyl)-N-methylcarbamate are obtained. Yield=95%.

c) Preparation of tert-Butyl (4′-formylbiphenyl-3-yl)methylcarbamate:

307 ml (615 mmol) of an aqueous potassium carbonate solution (2M) areadded dropwise to a mixture of 61.5 g (205 mmol) of tert-butyl(3-bromobenzyl)-N-methylcarbamate, 46 g (307 mmol) of4-formylbenzeneboronic acid and 500 ml of toluene. The reaction mediumis subsequently degassed with argon and 7 g (6.2 mmol) oftetrakis(triphenylphosphine)palladium(0) are added. After heating at 90°C. for 24 hours, the reaction medium is poured into water and extractedwith ethyl acetate. The organic phase is separated by settling, driedover magnesium sulfate and evaporated. The residue obtained is purifiedby chromatography on a silica column eluted with a mixture of heptaneand ethyl acetate (70/30). After evaporating the solvents, 67 g oftert-butyl (4′-formylbiphenyl-3-yl)methylcarbamate are collected.Yield=60%.

d) Preparation of tert-Butyl{4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-1(R)-hydroxy-3-oxopropyl]biphenyl-3-yl}methylcarbamate:

72.3 ml (72.3 mmol) of dibutylboron triflate and then 12.6 ml (72.3mmol) of diisopropylethylamine are added dropwise to a solution, cooledto 0° C., of 15.2 g (57.8 mmol) of(S)-4-benzyl-3-(2-ethoxyacetyl)oxazolidin-2-one, prepared as describedin the publication by Bernard Hulin et al., J. Med. Chem., 1996, 39,3897-3907, from commercial (S)-4-benzyloxazolidin-2-one, in 150 ml ofdichloromethane. The reaction medium is stirred at 0° C. for 30 min andthen cooled to −78° C. A solution of 15 g (48.2 mmol) of tert-butyl(4′-formylbiphenyl-3-yl)methylcarbamate in 70 ml of dichloromethane isthen added dropwise. After stirring from −78° C. to ambient temperatureover 4 hours, the reaction medium is cooled to 0° C. and a mixture of130 ml of a buffer solution, pH=7, and of 100 ml of methanol is addeddropwise, followed by the dropwise addition of a mixture of 130 ml ofaqueous hydrogen peroxide solution and of 100 ml of methanol. Thereaction medium is stirred at 0° C. for 1 hour and then at ambienttemperature for 3 hours. After addition of water, the reaction medium isextracted with dichloromethane. The organic phase is dried overmagnesium sulfate, filtered and evaporated under vacuum. The residueobtained is purified by chromatography on a silica column eluted with amixture of heptane and ethyl acetate (70/30) and then increase in thepolarity up to a 50/50 heptane/ethyl acetate mixture. After evaporationof the solvents, 28 g of tert-butyl{4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-1(R)-hydroxy-3-oxopropyl]biphenyl-3-yl}methylcarbamateare collected. Yield=81%.

e) Preparation of tert-Butyl(S)-{4′-[3-(4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-3-oxopropyl]biphenyl-3-yl}methylcarbamate:

4.8 ml (9.6 mmol) of sodium bis(trimethylsilylamide) are added dropwiseto a solution, cooled beforehand to 0° C., of 5 g (8.7 mmol) oftert-butyl{4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-1(R)-hydroxy-3-oxopropyl]biphenyl-3-yl}methylcarbamatein 70 ml of tetrahydrofuran. The reaction medium is stirred at −78° C.for 1 hour, then 1.3 ml (9.6 mmol) of phenyl chlorothionoformate areadded and the medium is stirred at −78° C. for 1 hour and then atambient temperature for 1 hour 30 min. After evaporation of thetetrahydrofuran, the reaction medium is extracted with dichloromethaneand washed with water. The organic phase is separated by settling, driedover magnesium sulfate, filtered and evaporated under vacuum. The 9 g(8.7 mmol) of residue obtained are placed in 100 ml of toluene and 71 mg(0.4 mmol) of 2,2′-azobis(2-methylpropionitrile) and then 3.5 ml (13.1mmol) of tributyltin hydride are added. The reaction medium is heated at110° C. for 20 minutes. After addition of water, the reaction medium isextracted with ethyl acetate. The organic phase is washed with water andwith a saturated aqueous sodium chloride solution, dried over magnesiumsulfate, filtered and evaporated. The residue obtained is purified bychromatography on a silica column eluted with a mixture of heptane andethyl acetate (90/10) and then increase in the polarity up to a 70/30heptane/ethyl acetate mixture. After evaporation of the solvents, 2.85 gof tert-butyl(S)-{4′-[3-(4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-3-oxopropyl]biphenyl-3-yl}methylcarbamateare obtained. Yield=60%.

f) Preparation of4(S)-Benzyl-3-[2(S)-ethoxy-3-(3′-(methylamino)biphenyl-4-yl)propionyl]oxazolidin-2-one:

9 ml (114 mmol) of trifluoroacetic acid are added dropwise to a solutionof 8.5 g (15.2 mmol) of(S)-{4′-[3-(4-benzyl-2-oxooxazolidin-3-yl)-2-ethoxy-3-oxopropyl]biphenyl-3-yl}methylcarbamatein 150 ml of dichloromethane. The reaction medium is stirred at ambienttemperature for 24 h, added to water and extracted with dichloromethane.The organic phase is dried over magnesium sulfate, filtered andevaporated. 8.7 g of4(S)-benzyl-3-[2(S)-ethoxy-3-(3′-(methylamino)biphenyl-4-yl)propionyl]oxazolidin-2-oneare obtained in the form of a trifluoroacetate salt. Yield=100%.

g) Preparation of1-{4′-[3-(4(S)-Benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphenyl-3-yl}-3-heptyl-1-methylurea:

1.1 ml (7.7 mmol) of triethylamine and then 2.25 ml (14.0 mmol) ofheptyl isocyanate are added dropwise to a solution of 4 g (7.0 mmol) of4(S)-benzyl-3-[2(S)-ethoxy-3-(3′-(methylamino)biphenyl-4-yl)propionyl]oxazolidin-2-onein 50 ml of dichloromethane. After stirring at ambient temperature for20 hours, the reaction medium is placed in water and extracted withdichloromethane. The organic phase is dried over magnesium sulfate,filtered and evaporated. The residue obtained is purified bychromatography on a silica column eluted with a mixture of heptane andethyl acetate (50/50). After evaporation of the solvents, 3.6 g of1-{4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphenyl-3-yl}-3-heptyl-1-methylureaare collected in the form of a colorless oil. Yield=86%.

h) Synthesis of2(S)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid:

18 ml (9.0 mmol) of a 0.5M aqueous lithium hydroxide solution are addedto a solution, cooled beforehand to 0° C., of 3.6 g (6.0 mmol) of1-{4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphenyl-3-yl}-3-heptyl-1-methylureain 80 ml of tetrahydrofuran. The reaction medium is stirred at 0° C. for2 hours, then a portion of the tetrahydrofuran is evaporated, and waterand n-butanol are added. The reaction medium is acidified with a 1Nhydrochloric acid solution to pH 3 and extracted with n-butanol. Theorganic phase is dried over magnesium sulfate, filtered and evaporatedunder vacuum. The residue obtained is purified by chromatography on asilica column eluted with a mixture of heptane and ethyl acetate (70/30)and then increase in the polarity up to a 50/50 heptane/ethyl acetatemixture. After evaporation of the solvents, 1.5 g of2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acidare collected in the form of a colorless oil. Yield=57%.

¹H NMR (δ, CDCl₃): 0.87 (t, J=7 Hz, 3H); 1.20-1.24 (m, 8H), 1.43 (m,2H), 3.12 (m, 1H), 3.18 (m, 1H), 3.22 (m, 2H), 3.32 (s, 3H), 3.49 (m,1H), 3.69 (m, 1H), 4.15 (m, 1H), 4.43 (m, 1H), 7.22-7.56 (m, 8H).

i) Preparation of L-Arginine salt of2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid:

An aqueous solution of 0.4 g (2.3 mmol) of L-arginine is added dropwiseto a solution, heated beforehand to 78° C., of 1 g (2.3 mmol) of2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acidin 22 ml of ethanol. The reaction medium is heated at 78° C. for 1 hour,then it is brought back to ambient temperature overnight and evaporatedto dryness under vacuum. The residue obtained is taken up in 15 ml ofethyl ether, stirred at ambient temperature for 30 min and filtered off.The solid obtained is rinsed with ethyl ether and dried under vacuum inan oven. 1.3 g of the L-arginine salt of2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acidare obtained in the form of a white powder. Yield=100%.

¹H NMR (δ, d₆-DMSO): 0.84 (m, 3H), 1.00 (m, 3H), 1.22 (m, 8H), 1.37 (m,2H), 1.27-1.39 (m, 4H), 2.90 (m, 1H), 2.97-3.07 (m, 3H), 3.18 (s, 3H),3.20 (m, 1H), 3.60 (m, 1H), 3.67 (m, 1H), 6.05 (m, 1H), 7.18-7.54 (m,8H).

Example 2 Synthesis of2(S)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid

a) Preparation of1-{4′-[3-(4(S)-Benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphenyl-3-yl}-1-methyl-3-pentylurea:

In a manner analogous to Example 1g), from 0.8 g (1.4 mmol) of4(S)-benzyl-3-[2(S)-ethoxy-3-(3′-(methylamino)biphenyl-4-yl)propionyl]oxazolidin-2-oneand 0.35 ml (2.8 mmol) of pentyl isocyanate, 0.54 g of1-{4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphenyl-3-yl}-1-methyl-3-pentylureais obtained in the form of a colorless oil. Yield=67%.

b) Synthesis of2(S)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid:

In a manner analogous to Example 1h), from 0.53 g (0.93 mmol) of1-{4′-[3-(4(S)-benzyl-2-oxooxazolidin-3-yl)-2(S)-ethoxy-3-oxopropyl]biphenyl-3-yl}-1-methyl-3-pentylureaand 2.8 ml (1.4 mmol) of a 0.5N aqueous sodium hydroxide solution, 0.32g of 2(S)-ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid is obtained in the form of a colorless oil. Yield=84%.

¹H NMR (δ, CDCl₃): 0.87 (t, J=7 Hz, 3H), 1.21 (t, J=7 Hz, 3H), 1.25-1.37(m, 8H), 1.60 (m, 2H), 3.11 (dd, J=7.8 Hz, J=14 Hz, 1H), 3.38 (dd, J=7Hz, J=14 Hz, 1H), 3.40 (m, 2H), 3.47 (m, 3H), 3.50 (m, 1H), 3.65 (m,1H), 4.15 (m, 1H), 6.94 (d, J=8.4 Hz, 1H), 7.35-7.40 (m, 3H), 7.75-7.82(m, 3H).

c) Preparation of L-Arginine salt of2(S)-ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid:

In a manner analogous to Example 1i), from 0.32 g (0.8 mmol) of2(S)-ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acidand 0.13 g (0.8 mmol) of arginine, 0.45 g of the L-arginine salt of2(S)-ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acidis obtained in the form of a white solid. Yield=100%.

¹H NMR (δ, d₆-DMSO): 0.86 (t, J=7 Hz, 3H), 1.01 (t, J=7 Hz, 3H),1.20-1.28 (m, 8H), 1.30 (m, 2H), 1.40 (m, 2H), 1.41-1.57 (m, 2H), 2.8(m, 1H), 3.00-3.10 (m, 4H), 3.20 (s, 3H), 3.22 (m, 1H), 3.33 (m, 1H),3.42 (m, 1H), 3.67 (m, 1H), 6.06 (m, 1H), 7.19-7.55 (m, 8H).

Example 3 Synthesis of2(S)-Cyclopropylmethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid

a) 3.6 g (12.7 mmol) of tert-butyl (3-bromophenyl)-N-methylcarbamate,prepared in a manner analogous to Example 1b), are dissolved in 15 ml ofdichloromethane. 5 ml of trifluoroacetic acid are added and the reactionmixture is stirred at ambient temperature for 1 hour. The reaction ishalted by the addition of 50 ml of a saturated sodium hydrogencarbonatesolution and then extraction is carried out with ethyl acetate. Theorganic phases are combined and dried over sodium sulfate. The solventsare evaporated and then the residue is chromatographed on silica gel(heptane/ethyl acetate 50/50). 2.14 g of 3-bromo-N-methylaniline areobtained in the form of an oil. Yield=90%.

b) 890 mg (3.5 mmol) of pinacolborane are added to a mixture of 600 mg(3.2 mmol) of 3-bromo-N-methylaniline and 1 g (10.2 mmol) of potassiumacetate in the presence of 130 mg (0.16 mmol, 5 mol %) of palladiumdichloride diphenylphosphinopropane ferrocene (PdCl₂dppf) in 10 ml ofdimethylformamide. The mixture is stirred at 90° C. for 2 hours. Thereaction is halted by the addition of 20 ml of water and then extractionis carried out with ethyl acetate. The organic phases are combined anddried over sodium sulfate. The solvents are evaporated and then theresidue is chromatographed on silica gel (heptane/ethyl acetate 80/20).420 mg ofmethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine areobtained in the form of an oil. Yield=57%.

c) 72 ml (0.122 mol, 2.5 eq) of tert-butyllithium (1.7M/pentane) areadded slowly using a needle to a suspension of 35 g (0.148 mol, 3 eq) of1,4-dibromobenzene in 100 ml of tert-butyl methyl ether at −30° C. Themixture is stirred at −30° C. for 10 min and then 5.3 g (0.059 mol) ofcopper(I) cyanide are introduced into the above solution. The reactionmixture is stirred at −30° C. for 20 min. A solution of 5 g (0.049 mol)of methyl (S)-glycidate in 10 ml of tert-butyl methyl ether is addedwhile keeping the temperature below −20° C. The mixture is stirred at−30° C. for 20 min and then the reaction is halted by the addition of asaturated ammonium chloride solution. The mixture is extracted with3×300 ml of ethyl acetate. The organic phases are combined and driedover sodium sulfate. The solvents are evaporated and then the residue ischromatographed on silica gel (heptane 100% up to heptane/ethyl acetate60/40). 7.2 g of methyl (S)-3-(4-bromophenyl)-2-hydroxypropionate areobtained in the form of a solid. Yield=56%.

d) 0.11 ml (1.15 mmol) of bromomethylcyclopropane are added to a mixtureof 267 mg (3.48 mmol) of silver oxide and 100 mg (0.38 mmol) of methyl(S)-3-(4-bromophenyl)-2-hydroxypropionate in 2 ml of diethyl ether. Thereaction mixture is stirred at 50° C. for 24 hours. The mixture isfiltered and then the solvents are evaporated. The residue ischromatographed on silica gel (heptane/ethyl acetate 85/15). 145 mg ofmethyl (S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propanoate areobtained in the form of an oil. Yield=50%.

e) 53 mg (0.046 mmol) of tetrakis(triphenylphosphine)palladium are addedto a solution of 145 mg (0.46 mmol) of methyl(S)-3-(4-bromophenyl)-2-(cyclopropylmethoxy)propionate and 129 mg (0.55mmol) ofmethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 3ml of dimethylformamide. 0.3 ml of a 2M potassium phosphate solution isadded and the reaction mixture is stirred at 90° C. for 2 hours. Thereaction is halted by the addition of 10 ml of water and then extractionis carried out with ethyl acetate. The organic phases are combined anddried over sodium sulfate. The solvents are evaporated and then theresidue is chromatographed on silica gel (heptane/ethyl acetate 80/20).70 mg of methyl(S)-2-cyclopropylmethoxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate areobtained in the form of an oil. Yield=45%.

f) 40 μl (0.25 mmol) of heptyl isocyanate are added to a solution of 70g (0.2 mmol) of methyl(S)-2-cyclopropylmethoxy-3-[3′-(methylamino)biphenyl-4-yl]propionate in2 ml of dichloromethane. The reaction mixture is stirred at ambienttemperature for 48 hours. The reaction is halted by the addition of 2 mlof water and then extraction is carried out with ethyl acetate. Theorganic phases are combined and dried over sodium sulfate. The solventsare evaporated and then the residue is chromatographed on silica gel(heptane/ethyl acetate 70/30). 86 mg of methyl(S)-2-cyclopropylmethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoateare obtained in the form of an oil. Yield=87%.

g) 21 mg (0.54 mmol) of sodium hydroxide are added to a solution of 86mg (0.18 mmol) of methyl(S)-2-cyclopropylmethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propionatein 2 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirredat ambient temperature overnight. The reaction is halted by the additionof 2 ml of water and 0.5 ml of acetic acid, and then extraction iscarried out with ethyl acetate. The organic phases are combined anddried over sodium sulfate. The solvents are evaporated and then theresidue is chromatographed on silica gel (dichloromethane/methanol90/10). 70 mg of2(S)-cyclopropylmethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid are obtained in the form of an oil. Yield=84%.

¹H NMR: (CDCl₃, 400 MHz): 0.20 (m, 2H), 0.56 (m, 2H), 0.86 (t, J=6.8 Hz,3H), 1.05 (m, 1H), 1.24 (m, 8H), 1.42 (m, 2H), 3.07-3.25 (m, 4H), 3.32(s, 3H), 3.39 (m, 2H), 4.20 (dd, J=4, 7.6 Hz, 1H), 4.40 (t, J=5.6 Hz,1H), 7.22 (d, J=7.6 Hz, 1H), 7.38 (d, J=8.4 Hz, 2H), 7.47-7.54 (m, 5H).

Example 4 Synthesis of2-(S)-Propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid

a) 0.22 ml (2.31 mmol) of propyl iodide is added to a mixture of 793 mg(3.48 mmol) of silver oxide and 300 mg (1.16 mmol) of methyl(S)-3-(4-bromophenyl)-2-hydroxypropionate in 3 ml of diethyl ether. Thereaction mixture is stirred at 50° C. for 12 hours. The mixture isfiltered and then the solvents are evaporated. The residue ischromatographed on silica gel (heptane/ethyl acetate 80/20). 291 mg ofmethyl (S)-3-(4-bromophenyl)-2-(propyloxy)propanoate are obtained in theform of an oil. Yield=83%.

b) 38 mg (0.033 mmol) of tetrakis(triphenylphosphine)palladium are addedto a solution of 100 mg (0.33 mmol) of methyl(S)-3-(4-bromophenyl)-2-(propyloxy)propionate and 90 mg (0.39 mmol) ofmethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 1ml of dimethylformamide. 0.2 ml of a 2M potassium phosphate solution isadded and the reaction mixture is stirred at 90° C. for 2 hours. Thereaction is halted by the addition of 10 ml of water and then extractionis carried out with ethyl acetate. The organic phases are combined anddried over sodium sulfate. The solvents are evaporated and then theresidue is chromatographed on silica gel (heptane/ethyl acetate 80/20).76 mg of methyl(S)-2-propyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtainedin the form of an oil. Yield=70%.

c) 156 μl (0.96 mmol) of heptyl isocyanate are added to a solution of210 mg (0.64 mmol) of methyl(S)-2-propyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate in 3 ml ofdichloromethane. The reaction mixture is stirred at ambient temperaturefor 48 hours. The reaction is halted by the addition of 2 ml of waterand then extraction is carried out with ethyl acetate. The organicphases are combined and dried over sodium sulfate. The solvents areevaporated and then the residue is chromatographed on silica gel(heptane/ethyl acetate 70/30). 200 mg of methyl(S)-2-propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoateare obtained in the form of an oil. Yield=66%.

d) 51 mg (1.28 mmol) of sodium hydroxide are added to a solution of 200mg (0.42 mmol) of methyl(S)-2-propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoatein 2 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirredovernight at ambient temperature. The reaction is halted by the additionof 2 ml of water and 0.5 ml of acetic acid, and then extraction iscarried out with ethyl acetate. The organic phases are combined anddried over sodium sulfate. The solvents are evaporated and then theresidue is chromatographed on silica gel (dichloromethane/methanol90/10). 147 mg of2-(S)-propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid are obtained in the form of an oil. Yield=76%.

¹H NMR (CDCl₃, 400 MHz): 0.86 (t, J=7.1 Hz, 3H), 0.90 (t, J=7.2 Hz, 3H),1.24 (m, 8H), 1.43 (m, 2H), 1.61 (sext, J=7 Hz, 2H), 3.07-3.22 (m, 4H),3.32 (s, 3H), 3.38 and 3.57 (2q, J=7.7 Hz, 2H), 4.13 (m, 1H), 4.41 (t,J=5.6 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.47-7.55(m, 5H).

Example 5 Synthesis of2(S)-Benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid

a) 1.9 ml (16 mmol) of benzyl bromide are added to a mixture of 4.4 g(19 mmol) of silver oxide and 3.5 g (13 mmol) of methyl(S)-3-(4-bromophenyl)-2-hydroxypropionate in 20 ml of diethyl ether. Thereaction mixture is stirred at 50° C. for 12 hours. The mixture isfiltered and then the solvents are evaporated. The residue ischromatographed on silica gel (heptane/ethyl acetate 80/20). 4 g ofmethyl (S)-3-(4-bromophenyl)-2-benzyloxypropanoate are obtained in theform of an oil. Yield=85%.

b) 635 mg (0.55 mmol) of tetrakis(triphenylphosphine)palladium are addedto a solution of 4 g (11 mmol) of methyl(S)-3-(4-bromophenyl)-2-benzyloxypropionate and 4 g (17 mmol) ofmethyl[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]amine in 25ml of dimethylformamide. 10 ml of a 2M potassium phosphate solution areadded and the reaction mixture is stirred at 70° C. for 1 hour. Thereaction is halted by the addition of 50 ml of water and then extractionis carried out with ethyl acetate. The organic phases are combined anddried over sodium sulfate. The solvents are evaporated and then theresidue is chromatographed on silica gel (heptane/ethyl acetate 80/20).2.6 g of methyl(S)-2-benzyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate are obtainedin the form of an oil. Yield=61%.

c) 2.25 ml (13.9 mmol) of heptyl isocyanate are added to a solution of2.6 g (6.95 mmol) of methyl(S)-2-benzyloxy-3-[3′-(methylamino)biphenyl-4-yl]propanoate in 15 ml ofdichloromethane. The reaction mixture is stirred at ambient temperaturefor 20 hours. The reaction is halted by the addition of 20 ml of waterand then extraction is carried out with ethyl acetate. The organicphases are combined and dried over sodium sulfate. The solvents areevaporated and then the residue is chromatographed on silica gel(heptane/ethyl acetate 70/30). 2.42 g of methyl(S)-2-benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoateare obtained in the form of an oil. Yield=67%.

d) 16 mg (0.4 mmol) of sodium hydroxide are added to a solution of 70 mg(0.42 mmol) of methyl(S)-2-benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoatein 2 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirredovernight at ambient temperature. The reaction is halted by the additionof 2 ml of water and 0.5 ml of acetic acid, and then extraction iscarried out with ethyl acetate. The organic phases are combined anddried over sodium sulfate. The solvents are evaporated and then theresidue is chromatographed on silica gel (dichloromethane/methanol90/10). 49 mg of2(S)-benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid are obtained in the form of an oil. Yield=72%.

¹H NMR (CDCl₃, 400 MHz): 0.86 (t, J=7 Hz, 3H), 1.24 (m, 8H), 1.43 (m,2H), 1.61 (sext, J=7 Hz, 2H), 3.10-3.26 (m, 4H), 3.33 (s, 3H), 4.24 (dd,J=4.4, 8 Hz, 1H), 4.44 (t, J=5.6 Hz, 1H), 4.48 and 4.73 (2d, J=11.6 Hz,2H), 7.21-7.30 (m, 6H), 7.37 (d, J=8.4 Hz, 2H), 7.47-7.55 (m, 5H).

Example 6 Synthesis of2(S)-Allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid

a) 100 mg of 10% palladium-on-charcoal are added to a solution of 2.4 g(4.66 mmol) of methyl(S)-2-benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoatein 10 ml of methanol. The reaction mixture is stirred overnight under ahydrogen atmosphere. The reaction mixture is filtered and then thesolvents are evaporated. The residue is filtered through silica gel(ethyl acetate). 1.61 g of methyl(S)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-hydroxypropionateare collected in the form of a colorless oil. Yield=81%.

b) 58 μl (0.70 mmol) of allyl bromide are added to a mixture of 162 mg(0.70 mmol) of silver oxide and 200 mg (0.47 mmol) of methyl(S)-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]-2-hydroxypropanoate in3 ml of diethyl ether. The reaction mixture is stirred at 40° C. for 24hours. The mixture is filtered and then the solvents are evaporated. Theresidue is chromatographed on silica gel (heptane/ethyl acetate 80/20 upto 60/40). 180 mg of methyl(S)-2-allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoateare obtained in the form of an oil. Yield=82%.

c) 56 mg (1.4 mmol, 3 eq) of sodium hydroxide are added to a solution of200 mg (0.47 mmol, 1 eq) of methyl(S)-2-allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoatein 2 ml of 9/1 THF/methanol. The reaction mixture is stirred at ambienttemperature for 3 hours. The reaction is halted by the addition of 2 mlof water and 0.5 ml of acetic acid, and then extraction is carried outwith ethyl acetate. The organic phases are combined and dried oversodium sulfate. The solvents are evaporated and then the residue ischromatographed on silica gel (dichloromethane/methanol 90/10). 152 mgof 2(S)-allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid are obtained in the form of an oil. Yield=78%.

¹H NMR (CDCl₃, 400 MHz): 0.86 (t, J=6.8 Hz, 3H), 1.26 (m, 8H), 1.42 (m,2H), 3.09-3.25 (m, 4H), 3.32 (s, 3H), 4.01 (dd, J=5.8, 12.6 Hz, 1H),4.16 (dd, J=5.7, 12.6 Hz, 1H), 4.22 (dd, J=4.3, 7.6 Hz, 1H), 4.41 (t,J=5.6 Hz, 1H), 5.22 (d, J=10.4 Hz, 1H), 5.25 (d, J=18.8 Hz, 1H), 5.83(m, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.37 (d, J=8.4 Hz, 2H), 7.52 (m, 5H).

Example 7 Crossed-Curve PPAR Transactivation Assay

Activation of the PPAR receptors by an agonist (activator) in HeLN cellsleads to the expression of a reporter gene, luciferase, which, in thepresence of a substrate, generates light. The modulation of the PPARreceptors is measured by quantifying the luminescence produced afterincubation of the cells in the presence of a reference agonist. Theligands will displace the agonist from its site. The measurement of theactivity is performed by quantifying the light produced. Thismeasurement makes it possible to determine the modulatory activity ofthe compounds according to the invention by the determination of theconstant which is the affinity of the molecule for the PPAR receptor.Since this value can fluctuate depending on the basal activity and theexpression of the receptor, it is referred to as apparent Kd (KdApp innM).

To determine this constant, “crossed curves” for the test product,against a reference agonist, are prepared using a 96-well plate: 10concentrations of the test product plus a concentration 0 are arrangedin a line, and 7 concentrations of the agonist plus a concentration 0are arranged in a column. This is 88 measurement points for 1 productand 1 receptor. The remaining 8 wells are used for repeatabilitycontrols.

In each well, the cells are in contact with a concentration of the testproduct and a concentration of the reference agonist,2-(4-{2-[3-(2,4-difluorophenyl)-1-heptylureido]ethyl}phenylsulfanyl)-2-methylpropionicacid for PPARα,{2-methyl-4-[4-methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5-ylmethylsulfanyl]phenoxy}aceticacid for PPARδ and5-{4-[2-(methyl(pyrid-2-yl)amino)ethoxy]benzyl}thiazolidine-2,4-dionefor PPARγ. Measurements are also taken for total agonist controls withthe same products.

The HeLN cell lines used are stable transfectants containing theplasmids ERE-βGlob-Luc-SV-Neo (reporter gene) and PPAR (α, δ, γ)Gal-hPPAR. These cells are seeded in 96-well plates at the rate of 10000 cells per well in 100 μl of DMEM medium without phenol red andsupplemented with 10% of defatted calf serum. The plates are thenincubated for 16 hours at 37° C. and 7% CO₂.

The various dilutions of the test products and of the reference ligandare added at the rate of 5 μl per well. The plates are subsequentlyincubated for 18 hours at 37° C. and 7% CO₂. The culture medium isremoved by turning over and 100 μl of a 1:1 PBS/luciferin mixture areadded to each well. After 5 minutes, the plates are read using theluminescence reader.

These crossed curves make it possible to determine the AC50 values(concentration at which 50% activation is observed) of the referenceligand at various concentrations of test product. These AC50 values areused to calculate the Schild regression by plotting a straight linecorresponding to the Schild equation (“Quantitation in ReceptorPharmacology”, Terry P. Kenakin, Receptors and Channels, 2001, 7,371-385) which allows the KdApp values (in nM) to be obtained.

Transactivation Results:

PPARα PPARδ PPARγ KdApp KdApp KdApp Compounds (in nM) (in nM) (in nm)Reference 1: 2-(4-{2-[3-(2,4- 200 n.a. n.a. difluorophenyl)-1-heptylureido]ethyl}phenylsulfany)- 2-methyl propionic acid Reference 2:{2-methyl-4-[4- n.a. 10 n.a. methyl-2-(4-(trifluoromethyl)phenyl)thiazol-5- ylmethylsulfanyl]phenoxy}acetic acidReference 3: 5-{4-[2- n.a. n.a. 30 (methyl(pyridin-2-yl)amino)ethoxy]benzyl}thiazolidine- 2,4-dione Example 1:2(S)-ethoxy-3-[3′-(3- 30 250 <1 heptyl-1-methylureido)biphenyl-4-yl]propionic acid Example 2: 2(S)-ethoxy-3-[3′-(1- 250 2000 0.03methyl-3-penylureido)biphenyl-4- yl]propionic acid Example 4:2-(S)-propyloxy-3-[3′- 30 500 0.025 (3-heptyl-1-methylureido)biphenyl-4- yl]propionic acid Example 5: 2-(S)-benzyloxy-3-250 n.a. 0.03 [3′-(3-heptyl-1- methylureido)biphenyl-4- yl]propionicacid Example 6: 2-(S)-allyloxy-3-[3′- 2 50 0.003 (3-heptyl-1-methylureido)biphenyl-4- yl]propionic acid n.a. means not active

TABLE 1 Compounds according to the present invention

Substituent as denoted in the present document KdApp in nM Compoundsaccording to Patent FR 2 812 876

Substituent as denoted in Patent FR 2 812 876 KdApp in nM Example 1 R1 =<1 Example 13 R10 = 500 2(S)-Ethoxy-3-[3′-(3- CH₂CH₃ (S)-2-Ethoxy-3-(3′-CH₂CH₃ heptyl-1- {[methyl(1- methylureido)biphenyl- phenylmethanoyl)4-yl]propionic acid amino]methyl} biphenyl-4- yl)propionic acid Example2 R2 = 0.03 Example 22 R4 = C(CH₃)₃ 250 2(S)-Ethoxy-3-[3′-(1- (CH₂)₄CH₃N-[4′-(2,4- methyl-3- Dioxothiazolidin-5- pentylureido)biphenyl-ylmethyl)biphenyl- 4-yl]propionic acid 3-ylmethyl]-2,2,N- trimethyl-propionamide Example 1 R2 = <1 Example 35 R4 = 10002(S)-Ethoxy-3-[3′-(3- (CH₂)₆CH₃ N-[4′-(2,4- (CH₂)₅CH₃ heptyl-1-Dioxothiazolidin-5- methylureido)biphenyl- ylmethyl)biphenyl-4-yl]propionic acid 3-ylmethyl]-N- methylheptanamide Example 4 R2 =0.025 Example 23 R4 = 2000 2(S)-propyloxy-3-[3′- (CH₂)₆CH₃N-Octyl-4′-(2,4- (CH₂)₇CH₃ (3-heptyl-1- dioxothiazolidin-5-methylureido)biphenyl- ylmethyl)biphenyl- 4-yl]propionic acid3-carboxamide Example 5 R2 = 0.03 Example 32 R4 = 2502(S)-benzyloxy-3-[3′- (CH₂)₆CH₃ N-[4′-(2,4- (CH₂)₈CH₃ (3-heptyl-1-Dioxothiazolidin-5- methylureido)biphenyl- ylmethyl)biphenyl-4-yl]propionic acid 3-ylmethyl]-N- methyldecanamide

These results show the affinity of the compounds for PPARγ and moreparticularly the specificity of the affinity of the compounds of theinvention for the PPARγ subtype, compared with the affinity of thecompounds for the PPARα subtype or for the PPARδ subtype.

Example 8 Compositions

Various specific formulations based on the compounds according to theinvention are illustrated in this example.

A—Oral Route:

(a) 0.2 g Tablet:

Compound of Example 1 0.001 g Starch 0.114 g Dicalcium phosphate 0.020 gSilica 0.020 g Lactose 0.030 g Talc 0.010 g Magnesium stearate 0.005 g

(b) Suspension to be Taken Orally in 5 ml Vials:

Compound of Example 5 0.001 g Glycerol 0.500 g 70% Sorbitol 0.500 gSodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.040 gFlavoring q.s. Purified water q.s. for 5 ml

(c) 0.8 g Tablet:

Compound of Example 2 0.500 g Pregelatinized starch 0.100 gMicrocrystalline cellulose 0.115 g Lactose 0.075 g Magnesium stearate0.010 g

(d) Suspension to be Taken Orally in 10 ml Vials:

Compound of Example 4 0.200 g Glycerol 1.000 g 70% Sorbitol 1.000 gSodium saccharinate 0.010 g Methyl para-hydroxybenzoate 0.080 gFlavoring q.s. Purified water q.s. for 10 ml

B—Topical Route:

(a) Salve:

Compound of Example 6 0.020 g Isopropyl myristate 81.700 g  Liquidpetrolatum 9.100 g Silica (“Aerosil 200”, marketed by Degussa) 9.180 g

(b) Salve:

Compound of Example 2 0.300 g White petrolatum, q.s. for 100 gpharmaceutical grade

(c) Nonionic Water-in-Oil Cream:

Compound of Example 1 0.100 g Mixture of emulsive lanolin 39.900 galcohols, of waxes and of oils (“Anhydrous eucerin”, marketed by BDF)Methyl para-hydroxybenzoate 0.075 g Propyl para-hydroxybenzoate 0.075 gSterile demineralized water q.s. for 100 g

(d) Lotion:

Compound of Example 3  0.100 g Polyethylene glycol (PEG) 400 69.900 g95% Ethanol 30.000 g

(e) Hydrophobic Salve:

Compound of Example 5 0.300 g Isopropyl myristate 36.400 g Silicone oil(“Rhodorsil 47 V 300”, 36.400 g marketed by Rhone-Poulenc) Beeswax13.600 g Silicone oil (“Abil 300,000 cSt”, q.s. for 100 g marketed byGoldschmidt)

(f) Nonionic Oil-in-Water Cream:

Compound of Example 2 1.000 g Cetyl alcohol 4.000 g Glycerylmonostearate 2.500 g PEG 50 stearate 2.500 g Shea butter 9.200 gPropylene glycol 2.000 g Methyl para-hydroxybenzoate 0.075 g Propylpara-hydroxybenzoate 0.075 g Sterile demineralized water q.s. for 100 g

Each patent, patent application, publication, text and literaturearticle/report cited or indicated herein is hereby expresslyincorporated by reference.

While the invention has been described in terms of various specific andpreferred embodiments, the skilled artisan will appreciate that variousmodifications, substitutions, omissions, and changes may be made withoutdeparting from the spirit thereof. Accordingly, it is intended that thescope of the present invention be limited solely by the scope of thefollowing claims, including equivalents thereof.

1. A method for the activation of receptors of PPARγ, comprisingcontacting said receptors with an effective PPARγ receptor-activatingamount of a biaromatic compound having the following structural formula(I):

in which: R1 is an alkyl radical selected from the group consisting ofmethyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl, tert-butyl,n-pentyl, isopentyl, n-hexyl, isohexyl, cyclohexyl, ethylenyl, allyl,propenyl, butenyl, pentenyl and hexenyl, or an acetyl group or amethylcyclopropane group; R2 is an alkyl radical having 3 to 8 carbonatoms; R3 is a hydrogen atom or an alkyl radical having 1 to 6 carbonatoms; R4 and R5, which are identical or different, are each a hydrogenatom, a halogen atom, a hydroxyl radical, an alkyl radical having from 1to 6 carbon atoms, an alkoxy radical, a benzyloxy radical or atrifluoromethyl radical; or an isomer, optical or geometrical, pure oras a mixture, in any proportion, of said compound of formula (I) or atautomeric form, or a salt of said compound of formula (I).
 2. Themethod as defined by claim 1, wherein the compound having formula (I) isin the form of an alkali metal salt or an alkaline earth metal salt oran organic amine salt thereof.
 3. The method as defined by claim 1,wherein the compound having formula (I) is in the form of a sodium saltthereof.
 4. The method as defined by claim 1, wherein the compoundhaving formula (I) is in the form of an amino acid salt thereof.
 5. Themethod as defined by claim 1, wherein the compound having formula (I) isin the form of an arginine salt or a lysine salt thereof.
 6. The methodas defined by claim 1, wherein, in the compound having formula (I), R2is selected from the group consisting of n-propyl, isopropyl,cyclopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl,cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl, isoheptyl,n-octyl, isooctyl, allyl, propenyl, butenyl, pentenyl, hexenyl, heptenyland octenyl radicals.
 7. The method as defined by claim 1, wherein thecompound having formula (I) bears a fluorine, bromine or chlorine atomsubstituent.
 8. The method as defined by claim 1, wherein the compoundhaving formula (I) bears a methoxy, ethoxy, isopropyloxy, tert-butoxy,or hexyloxy radical substituent.
 9. The method as defined by claim 1,wherein the compound having formula (I) is selected from the groupconsisting of:2(S)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid,2(S)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid,2(S)-Cyclopropylmethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(S)-Propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(S)-Allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(S)-Cyclopropylmethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,3-[3′-(1-Methyl-3-pentylureido)biphenyl-4-yl]-2(S)-propoxypropanoicacid,2(S)-Allyloxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Methoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,3-[3′-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropanoicacid, 2(S)-Ethoxy-3-[3′-(1-methyl-3-propylureido)biphenyl-4-yl]propanoicacid,3-[3′-(3-Cyclopropylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid,3-[3′-(3-Cyclopentylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid,2(S)-Ethoxy-3-[3-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Ethoxy-3-[4′-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,3-[3,4′-Difluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid, Methyl2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate,Methyl2(S)-cyclopropylmethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoate,2(S)-Cyclopropylmethoxy-3-[3′-(3-cyclopropylmethyl-1-methylureido)biphenyl-4-yl]propanoicacid,3-{3′-[3-(2-Cyclohexylethyl)-1-methylureido]biphenyl-4-yl}-2(S)-ethoxypropanoicacid, 2(R)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid, 2(R)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid, 2-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(R)-Allyloxy-3[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid, 3-[3′-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid, and Allyl3-[3′-(3-allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoate. 10.The method as defined by claim 1, wherein the compound having formula(I) has at least one of the following characteristics: R1 is a methyl,ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl or tert-butyl radical,or a methylcyclopropane group, R2 is a n-pentyl, isopentyl, cyclopentyl,n-hexyl, isohexyl, cyclohexyl, n-heptyl or isoheptyl radical, R3 is ahydrogen atom, R4 and/or R5 are each a hydrogen atom or a fluorine atom.11. The method as defined by claim 1, wherein, in the compound havingformula (I), R1 is an alkyl radical selected from the group consistingof methyl, ethyl, n-propyl, isopropyl, cyclopropyl, isobutyl,tert-butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, cyclohexyl,ethylenyl, allyl, propenyl, butenyl, pentenyl and hexenyl.
 12. Themethod as defined by claim 11, wherein R1 is an alkyl radical selectedfrom the group consisting of methyl, ethyl, n-propyl, isopropyl,cyclopropyl, isobutyl and tert-butyl.
 13. A method for the activation ofreceptors of PPARγ, comprising contacting said receptors with aneffective PPARγ receptor-activating amount of a biaromatic compoundhaving the following structural formula (I):

in which: R1 is a methyl, ethyl, propyl or allyl radical; R2 is an alkylradical having 3 to 8 carbon atoms; R3 is a hydrogen atom or an alkylradical having 1 to 6 carbon atoms; R4 and R5, which are identical ordifferent, are each a hydrogen atom, a halogen atom, a hydroxyl radical,an alkyl radical having from 1 to 6 carbon atoms, an alkoxy radical, abenzyloxy radical or a trifluoromethyl radical; or an isomer, optical orgeometrical, pure or as a mixture, in any proportion, of said compoundof formula (I) or a tautomeric form, or a salt of said compound offormula (I).
 14. The method as defined by claim 11, wherein, in thecompound having formula (I), R2 is an alkyl radical selected from thegroup consisting of n-pentyl, isopentyl, cyclopentyl, n-hexyl, isohexyl,cyclohexyl, n-heptyl and isoheptyl.
 15. The method as defined by claim12, wherein, in the compound having formula (I), R2 is an alkyl radicalselected from the group consisting of n-pentyl, isopentyl, cyclopentyl,n-hexyl, isohexyl, cyclohexyl, n-heptyl and isoheptyl.
 16. The method asdefined by claim 13, wherein, in the compound having the formula (I), R2is an alkyl radical selected from the group consisting of n-pentyl,isopentyl, cyclopentyl, n-hexyl, isohexyl, cyclohexyl, n-heptyl andisoheptyl.
 17. The method as defined by claim 11, wherein, in thecompound having the formula (I), R3 is a hydrogen atom.
 18. The methodas defined by claim 12, wherein, in the compound having the formula (I),R3 is a hydrogen atom.
 19. The method as defined by claim 13, wherein,in the compound having the formula (I), R3 is a hydrogen atom.
 20. Themethod as defined by claim 11, wherein, in the compound having theformula (I), R4 and R5, which are identical or different, are each ahydrogen atom or a fluorine atom.
 21. The method as defined by claim 12,wherein, in the compound having the formula (I), R4 and R5, which areidentical or different, are each a hydrogen atom or a fluorine atom. 22.The method as defined by claim 13, wherein, in the compound having theformula (I), R4 and R5, which are identical or different, are each ahydrogen atom or a fluorine atom.
 23. The method as defined by claim 14,wherein, in the compound having the formula (I), R3 is a hydrogen atom.24. The method as defined by claim 15, wherein, in the compound havingthe formula (I), R3 is a hydrogen atom.
 25. The method as defined byclaim 16, wherein, in the compound having the formula (I), R3 is ahydrogen atom.
 26. The method as defined by claim 14, wherein, in thecompound having the formula (I), R4 and R5, which are identical ordifferent, are each a hydrogen atom or a fluorine atom.
 27. The methodas defined by claim 15, wherein, in the compound having the formula (I),R4 and R5, which are identical or different, are each a hydrogen atom ora fluorine atom.
 28. The method as defined by claim 16, wherein, in thecompound having the formula (I), R4 and R5, which are identical ordifferent, are each a hydrogen atom or a fluorine atom.
 29. The methodas defined by claim 17, wherein, in the compound having the formula (I),R4 and R5, which are identical or different, are each a hydrogen atom ora fluorine atom.
 30. The method as defined by claim 18, wherein, in thecompound having the formula (I), R4 and R5, which are identical ordifferent, are each a hydrogen atom or a fluorine atom.
 31. The methodas defined by claim 19, wherein, in the compound having the formula (I),R4 and R5, which are identical or different, are each a hydrogen atom ora fluorine atom.
 32. The method as defined by claim 13, wherein, in thecompound having the formula (I), R1 is ethyl.
 33. The method as definedby claim 30, wherein the compound having formula (I) is2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid.34. The method as defined by claim 13, wherein the compound havingformula (I) is selected from the group consisting of:2(S)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid,2(S)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid,2(S)-Propyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(S)-Allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,3-[3′-(1-Methyl-3-pentylureido)biphenyl-4-yl]-2(S)-propoxypropanoicacid,2(S)-Allyloxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Methoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,3-[3′-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropanoicacid, 2(S)-Ethoxy-3-[3′-(1-methyl-3-propylureido)biphenyl-4-yl]propanoicacid,3-[3′-(3-Cyclopropylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid,3-[3′-(3-Cyclopentylmethyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid,2(S)-Ethoxy-3-[3-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Ethoxy-3-[4′-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,3-[3,4′-Difluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid, Methyl2(S)-ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate,3-{3′-[3-(2-Cyclohexylethyl)-1-methylureido]biphenyl-4-yl}-2(S)-ethoxypropanoicacid, 2(R)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid, 2(R)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid, 2-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(R)-Allyloxy-3[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid, 3-[3′-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid, and Allyl3-[3′-(3-allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoate. 35.A method for the activation of PPARγ, comprising contacting saidreceptors with an effective PPARγ receptor-activating amount of abiaromatic compound having the following structural formula (I):

in which: R1 is methyl, ethyl, allyl, cyclopropylmethyl or benzyl; R2 isn-pentyl or n-heptyl; R3 is hydrogen; R4 and R5, which are identical ordifferent, are a hydrogen atom or a fluorine atom; and the compound hasthe (S) configuration at the 2-position of the propionic acid portion ofthe molecule.
 36. The method as defined by claim 43, wherein thecompound having formula (I) is selected from the group consisting of:2(S)-Ethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid,2(S)-Ethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoic acid,2(S)-Cyclopropylmethoxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(S)-Benzyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(S)-Allyloxy-3-[3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoicacid,2(S)-Cyclopropylmethoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Allyloxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Benzyloxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Methoxy-3-[3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,3-[3′-(3-Heptyl-1-methylureido)biphenyl-4-yl]-2(S)-methoxypropanoicacid,2(S)-Ethoxy-3-[3-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,2(S)-Ethoxy-3-[4′-fluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]propanoicacid,3-[3,4′-Difluoro-3′-(1-methyl-3-pentylureido)biphenyl-4-yl]-2(S)-ethoxypropanoicacid, and3-[3′-(3-Allyl-1-methylureido)biphenyl-4-yl]-2(S)-ethoxypropanoic acid.37. A method according to claim 1 for the activation of receptors ofPPARγ and thus for regulating and/or restoring the metabolism of skinlipids, comprising administering to an individual in need of suchtreatment, said effective PPARγ receptor-activating amount of saidcompound having the formula (I), formulated into a physiologicallyacceptable medium therefor.
 38. A method according to claim 1 for theactivation of receptors of PPARγ and thus for the treatment of: commonacne, comedo-type acne, polymorphic acne, rosacea, nodulocystic acne,acne conglobata, senile acne or secondary acne, ichthyosis, anichthyosiform condition, Darier's disease, palmoplantar keratoderma,leukoplakia, a leukoplakiform condition, cutaneous lichen or mucosal(oral) lichen; cutaneous psoriasis, mucosal psoriasis, ungual psoriasis,psoriatic rheumatism, eczema or other cutaneous atopy, respiratory atopyor gingival hypertrophy; common warts, flat warts, epidermodysplasiaverruciformis, oral or florid papillomatoses, T lymphoma; basal cell orspinocellular epithelioma or keratoacanthomas; lupus erythematosus,bullous immune disease or scleroderma; an actinic keratosis,pigmentation or xerosis; the hyperseborrhoea of acne, simple seborrhoeaor seborrheoic dermatitis, a cicatrization disorder or stretch marks;hyperpigmentation, melasma, hypopigmentation or vitiligo; obesity,hyperlipidaemia or non-insulin-dependent diabetes; arthritis; acancerous or precancerous condition; alopecia; asthma, type I sugardiabetes or multiple sclerosis; or arteriosclerosis or hypertension;comprising administering to an individual in need of such treatment,said effective PPARγ receptor-activating amount of said compound havingformula (I), formulated into a physiologically acceptable supporttherefor.